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Adipose-derived stem cells (ASCs) isolated from subcutaneous adipose tissue have been tested in clinical trials. However, ASCs isolated by enzyme digestion and centrifugation are heterogeneous and exhibit wide variation in regenerative potential and clinical outcomes. Therefore, we developed a new method for isolating clonal ASCs (cASCs) that does not use enzyme digestion or centrifugation steps.In addition to cell surface markers and differentiation potential, we compared the mitogenic, paracrine and hair growth-promoting effects of ASCs isolated by the gradient centrifugation method (GCM) or by the new subfractionation culturing method (SCM).We selected three cASCs isolated by SCM that showed high rates of proliferation. The cell surface markers expressed by ASCs isolated by GCM or SCM were very similar, and SCM-isolated ASCs could potentially differentiate into different cell lineages. However, cASC lines exhibited better mitogenic and paracrine effects than ASCs isolated by GCM. The expression of Diras3, Myb, Cdca7, Mki67, Rrm2, Cdk1 and Ccna2, which may play a key role in cASC proliferation, was upregulated in cASCs. In addition, cASCs exhibited enhanced hair growth-promoting effects in dermal papilla cells and animal experiments.SCM generates a highly homogeneous population of ASCs via a simple and effective procedure that can be used in therapeutic settings.

Several lines of evidence suggest that VEGF is a key regulator of the paracrine effects of adipose-derived stem cells (ASCs), but the mechanism of action remains to be identified.This brief review discusses the following research questions: i) Does VEGF increase the proliferation/migration and differentiation of ASCs?; ii) Does VEGF mediate the paracrine effects of ASCs?; and iii) How is VEGF synthesized, and which factors regulate VEGF secretion?External stimuli such as hypoxia may activate receptor tyrosine kinases in the membrane of ASCs, which, in turn, phosphorylate extracellular signal regulated kinase (ERK) and members of the Akt signaling pathway, stabilizing hypoxia inducible factor 1α (HIF-1α) that are primary regulators of VEGF expression. Secreted VEGF directly stimulates ASCs via VEGF receptors in an autocrine manner and regenerates damaged neighboring cells in a paracrine manner.Most studies of stem cell regeneration have focused on differentiation of ASCs and their building block function; however, the paracrine effects of ASCs should also be the focus of attention.

Adipose tissue is one of the richest sources of mesenchymal stem cells. Even more interesting is the fact that adipose-derived stem cells (ASCs) show an outstanding ability to regenerate damaged skin. Thus, ASCs are a popular and feasible treatment in clinical dermatology.This review discusses the potential applications of ASCs and conditioned medium of ASC (ASC-CM) to skin, and briefly touches on the mechanisms by which ASCs promote skin regeneration.Clinically, processed lipo-aspirated (PLA) cells are commonly used for treatment of aged skin; however, the use of PLA cells for cosmetic purposes is not convenient, because PLA cells are prepared from patients. Alternatively, cosmetics that contain ASC-CM can be pre-made from healthy volunteers such that they are immediately available for clinical treatment of aged skin. Cell-based therapies are adequate for improvement of wrinkles or for soft tissue augmentation, whereas ASC-CM has merit for amelioration of skin tone. When culturing ASCs for the production of cosmetic raw materials, hypoxic culture conditions and transduction of specific genes into ASCs may increase the regenerative protein content of the conditioned medium.Application of ASCs and ASC-CM to dermatology shows promising results for skin regeneration.

The aim of tissue engineering is to repair and regenerate damaged organs using a combination of cells, biomaterials and growth factors. Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue, that is adipose-derived stem cells (ADSCs) have been used in skin repair with satisfactory results. The production and secretion of growth factors has been reported to be an essential function of ADSCs, and diverse regenerative effects of ADSCs in the skin have been demonstrated.Recent research developments concerning the wound-healing and antioxidant effects of ADSCs are briefly described.Various experimental results regarding the wound-healing and antioxidant effect of ADSCs are introduced, and the mechanisms and identification of active proteins involved in these function are further discussed.Evidence of ADSC differentiation of skin has not been reported in vivo, but ADSCs accelerate wound-healing and exhibit antioxidant effects under various conditions. The wound-healing and antioxidant effects of ADSCs are mainly mediated by the activation of dermal fibroblasts and keratinocytes via the paracrine mechanism. Since ADSCs are easily obtained in large quantities and have an advantage over other stem cell sources, ADSCs and their secretory factors show promise for use in skin repair and regeneration.

The self-renewal and differentiation of stem cells are controlled by both intrinsic factors and the surrounding microenvironment, which is known as the stem cell niche. Although the niches of adipose-derived stem cells (ASCs) are composed of diverse factors within the adipose tissue, the mechanisms by which niches are maintained, regulated and harmonized to support the ASCs are just beginning to be discovered.This review introduces the recent advances in the anatomic nature of the dynamic in vivo niches of ASCs. Additionally, new findings concerning the signaling pathways involved in the self-renewal, proliferation, differentiation and paracrine mechanisms will be described. Finally, we suggest optimized methods for expanding ASCs in vitro by mimicking the niche factors to enhance the regenerative potential of ASCs.Fibroblast growth factor 2 is a self-renewal factor that can expand the lifespan of ASCs in long-term culture and platelet-derived growth factor-B/D has most potent mitogenic effects on short-term ASC expansion. Reactive oxygen species donors and stimulators of the phosphoinositide 3-kinase/protein kinase B and MAPK pathways can be used to increase the production yield of ASCs. Additionally, hypoxia can increase the proliferation of ASCs and priming under hypoxic conditions enhances the regenerative potential of ASCs.

A stem cell (SC) niche is defined as the microenvironment in which the adult SC resides and includes surrounding cells, low oxygen content and growth factor gradients. Crosstalk between SCs and their niche provides signals that keep SCs quiescent, or modulates their activation.This review discusses the characterization of niche conditions in the adipose-derived stem cell (ASC) in vivo environment, and introduces key signalling pathways and autocrine/paracrine regulators of ASCs.Control of in vivo niche factors (such as low oxygen content, generation of reactive oxygen species and activation of platelet-derived growth factor receptor signalling) should increase ASC yields synergistically and reduce production costs. Additionally, the preconditioning of ASCs with these niche factors prior to transplantation might enhance their regenerative potential. ASC niche is complex, and there are components of the niche that we may not yet understand. Therefore, future research needs to focus on identifying the key regulatory factors of the ASC niche in vivo, and developing a novel method to mimic these niche factors for in vitro manipulation.

Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue (i.e., adipose-derived stem cells (ASCs)), have been used for tissue engineering. In addition to serving a building-block function, ASCs are reported to secrete growth factors that are essential for their function. Increasing evidence indicates that ASCs play a significant role in skin regeneration, a function that is enhanced by hypoxia through upregulating secretion of growth factors. Although the anatomical sites of ASCs in the body are relatively oxygen-deficient, ASCs are usually cultured under normoxic conditions (i.e., atmospheric oxygen levels). Culturing ASCs under physiologically relevant low-oxygen-tension conditions may uniquely benefit the expansion, differentiation, adhesion, growth factor secretion and regenerative potential of ASCs. Therefore, understanding the response and adaptation of ASCs to hypoxia may be invaluable for developing novel cell- and cyto-therapy strategies. This review highlights our current understanding of cellular and molecular responses of ASCs to hypoxia, focusing on the enhancement of ASC function and secretory activity by hypoxic culture conditions.